ABOUT THE AUTHOR

Dr. Henry is a vitreoretinal surgeon and uveitis fellow at the Bascom Palmer Eye Institute, Miami.




Dr. Albini is an associate professor of ophthalmology, vitreoretinal surgeon and uveitis specialist at the Bascom Palmer Eye Institute.  


Disclosures: Dr. Albini receives consulting fees from Bausch + Lomb, Allergan and Santen. 

Severe vision loss can occur in 25 to 33 percent of uveitis cases, making it one of the most common causes of preventable blindness in the developing world.1,2 Traditional systemic immunosuppressive therapy for posterior segment uveitis, allowing successful control of inflammation at one year, is successful in 60 to 70 percent of cases.1 With acceptable use of less than 10 mg of oral prednisone daily, these therapies are effective in 40 to 60 percent of cases.1,2

Despite the effectiveness of systemic therapy for non-infectious uveitis, still 10 to 25 percent of patients taking immunomodulatory medications for control of uveitis will discontinue these medications within one year because of side effects.1 Fortunately, local therapies can assist us in controlling disease and new therapies are continuing to be developed to assist us in this mission. In the past year new data has significantly added to our understanding of local treatment of noninfectious uveitis.  

Recent updates on the fluocinolone acetonide intravitreal implant (Retisert, Bausch + Lomb), dexamethasone intravitreal implant (Ozurdex, Allergan) and intravitreal sirolimus (Santen) have provided us with additional data on the relative risks and benefits of these therapeutic options.  The 54-month data from the Multicenter Uveitis Steroid Treatment (MUST) trial confirms that the fluocinolone implant works at least as well as systemic therapy. Additionally, data concerning local injection of sirolimus have shown efficacy and the dexamethasone implant is shown to work well for uveitic cystoid macular edema.

MUST Trial 54-Month Update
The MUST trial is a 23-center, partially masked, randomized controlled trial comparing the safety and efficacy of the fluocinolone implant and systemic therapy with oral corticosteroids and immunosuppressive medications for patients with severe noninfectious intermediate uveitis, posterior uveitis or panuveitis.3 The initial study randomized 255 patients (479 eyes) from 2005-2008 to either the surgical implant (129 patients) or systemic therapy (126 patients).   

Twenty-four month follow-up found similar visual acuity outcomes results between the two groups.4 Through 24 months, the implant group had superior control of intraocular inflammation, but also had a significantly higher risk of requiring cataract surgery, needing treatment for elevated intraocular pressure and developing glaucoma. The systemic therapy group had higher rates of infections requiring prescriptions.4

Three-year cost-effectiveness analysis found that systemic therapy was more cost-effective for patients with bilateral disease, but that both were similarly cost effective in patients with unilateral disease.5

The 54-month MUST results give us continued reports on the utility of the fluocinolone acetonide implant.6 Best-corrected visual acuity data was available in 101 patients (190 eyes) who received the implant and 96 patients (179 eyes) who received systemic treatment. The study found no statistical difference between the groups, with both groups having a mean improvement of around 0.5 lines of vision.  

Visual acuity gains were limited, in part, by the fact that 50 percent of uveitis eyes had a baseline vision of 20/40 or better. Among patients with worse than 20/40 vision, visual acuity results were also similar between the two groups, as was visual field sensitivity—with the exception of those in the lower quartile for mean deviation, where the implant group fared worse.  

Like the 24-week results, the implant group had a statistically significant improvement in inflammatory control compared to the systemic group through 54 months. Vitreous cells and haze improved in both groups over time, but the implant group had a higher likelihood of having a vitreous haze score of zero and had a greater improvement in the degree of vitreous cells.  

The proportion of patients with macular edema was not statistically different between the two groups at 54 months compared to baseline, although macular edema improved more quickly in the implant group based on six-month follow-up data. Despite the expected three-year duration of action of the implant, only 10 percent of the implant group eyes required additional implant exchange over the 54-week follow-up.6

 
Figure. A 55-year-old woman was treated for intermediate uveitis and retinal vasculitis with mycophenolate mofetil and oral prednisone. Upon attempted taper of oral prednisone, the patient developed recurrent retinal vasculitis (A). The patient underwent an intravitreal Ozurdex injection. Ten weeks after the Ozurdex injection, the retinal vasculitis was dramatically improved (B).
Implant Side Effects
A companion study compared the side effects and quality-of-life measures between systemic therapy and the fluocinolone acetonide implant over the 54-week follow up.7 This study found that the incidence of elevated IOP, glaucoma, use of IOP-lowering therapy and need for IOP-lowering surgery were all significantly higher in the implant group.

Development of cataract was almost universal in the implant group, with 87.7 percent of eyes having had cataract surgery compared to 43 percent in the systemic group. Systemic side effects were similar between both arms and specifically not higher among the systemic immunosuppression group. Quality-of-life measures were similar among the two groups.7

The companion study authors suggested that systemic therapy may be preferable to the implant in patients with bilateral disease due to superior cost-effectiveness and fewer ocular side effects. Nevertheless, the fluocinolone acetonide implant remains a viable treatment option, particularly in cases of unilateral disease, among those who cannot receive systemic therapy, as well as among those who fail systemic treatment.  

Preliminary results of a Phase III trial of a second fluocinolone sustained-release device, the Medidur fluocinolone insert (pSivida Corp.), reported the device met its primary endpoint of prevention of recurrence at six months in the treatment of posterior noninfectious uveitis.8 The trial will continue to follow patients for three years, and we will learn more about the rate of local complications of the two implants.

Dexamethasone for Uveitic CME  
Rahul Khurana, MD, reported on one-year results of the TAHOE (prospective evaluation of susTained-release dexAmetHasone intravitreal implant fOr uveitis macular Edema) study at the Retina Society 2015 meeting in Paris.9 The TAHOE study is a prospective, noncomparative, interventional trial assessing the effectiveness of a 0.7-mg dexamethasone intravitreal implant for treatment of persistent cystoid macular edema in eyes with quiescent uveitis.  

Ten patients were treated with the dexamethasone  implant. They were monitored monthly and retreated with the implant after day 90 days if any recurrent CME was noted on optical coherence tomography.  Average presenting findings were: visual acuity, 20/63; and central subfield macular thickness, 481 μm. At three-month follow-up, average vision improvement was 14 letters (p=0.0001). At 12 months, two-thirds of eyes had improved by 3 or more lines of vision.  

Over the 12-month follow-up, patients required an average of two dexamethasone injections to control macular edema, although four patients required only a single injection. The mean time to recurrence of CME was 6.3 months. One eye had an IOP rise greater than 25 mmHg, and two of eight phakic eyes had cataract surgery due to cataract progression. Results of this study suggest that the 0.7-mg dexamethasone implant was effective in treating persistent CME in quiescent uveitis eyes, although future comparative trials involving other treatments are needed.  

Take-home Point
The development of new intravitreal therapies for non-infectious uveitis is encouraging. Three recent studies have indicated that an increasing number of local treatments are or will soon be available for chronic noninfectious uveitis involving the posterior segment. Whether used as monotherapy or as an adjunct to systemic therapy, these agents will provide the uveitis specialist with increased options, especially for patients who cannot tolerate traditional systemic immunosuppression or want to avoid it.
SAKURA Intravitreal Sirolimus Trial
SAKURA (Study Assessing Double-masked Uveitis Treatment) is a multicenter, double-masked randomized trial assessing the safety and efficacy of intravitreal sirolimus for treatment of noninfectious posterior segment uveitis.1 Sirolimus acts as an mTor inhibitor that disrupts T-cell proliferation and the release of IL-2 and other inflammatory cytokines.10,11 Phase III results are now available.1

The study had a monotherapy design in which a 44-ug intravitreal preparation of sirolimus served as an active treatment control group and was evaluated against 440-ug and 880-ug intravitreal sirolimus preparations. The study remained masked through six months, during which patients in each group received injections at baseline, two months and four months.

The primary endpoint was a vitreous haze score of zero at month five in the study eye. To be included in the study, patients were required to have a presenting vitreous haze score of greater than one and 20/400 BCVA or worse in the study eye. Patients ceased immunomodulatory therapy at least 30 days before the first day of the study, and topical corticosteroids were tapered before day one.

The intent-to-treat population included 117 patients in the 44-ug group, 114 in the 440-ug group and 117 in the 880-ug group. At five months, 22.8 percent of patients in the 400-ug group achieved a vitreous haze score of zero compared to 10.3 percent of the 44-ug group (p=0.025). In contrast, only 16.4 percent of
patients in the 880-ug group achieved a vitreous haze score of zero.  

Sixty-nine patients in the series were taking at least 7.5 mg of oral prednisone at baseline and were studied on an intent-to-taper basis. Twenty of 26 patients (76.9 percent) in the 440-ug group were tapered to less than 5 mg/day of oral prednisone without needing rescue therapy compared to 14 of 22 (63 percent) of patients in the 44-ug group, but this result was not statistically significant.   

ERM Influence On Central Retinal Thickness

This study also evaluated the change in central retinal thickness, although it was not a primary or secondary outcome. The greatest improvements in central macular thickness were seen in patients without an epiretinal membrane receiving the 440-ug dose of sirolimus, in whom the reduction was greater than 50 percent, whereas those in the 44-ug group showed a reduction in central macular thickness of less than 5 percent.

In patients with an ERM, the reduction in central macular thickness was similar between the 440-ug and 44-ug-dose groups. Increase in IOP of greater than 35 mmHg persisting more than seven days was seen in only one patient in each the 44-ug and 440-ug groups (0.9 percent of each group) and three patients (2.6 percent) in the 880-ug group. RS

REFERENCES
1. Albini TA. Key outcomes of SAKURA study 1: A phase 3 study of intravitreal sirolimus for non-infectious uveitis of the posterior segment. Paper presented at: American Academy of Ophthalmology 2014 Annual Meeting; October 15, 2014; Chicago, IL.
2. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.
3. The Multicenter Uveitis Steroid Treatment Trial Research Group.  The Multicenter Uveitis Steroid Treatment (MUST) trial: rationale, design, and baseline characteristics. Am J Ophthalmol. 2010;149:550-651.     
4. The Multicenter Uveitis Steroid Treatment Trial Research Group, Kempen JH, Altaweel MM, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the multicenter uveitis steroid treatment trial. Ophthalmology 2011;118:1916–1926.
5. The Multicenter Uveitis Steroid Treatment Trial Follow-up Study Research Group. Cost-effectiveness of fluocinolone acetonide implant versus systemic therapy for noninfectious intermediate, posterior, and panuveitis. Ophthalmology 2014;121:1855–62.
6. The Multicenter Uveitis Steroid Treatment Trial Research Group. Benefits of systemic anti-inflammatory therapy versus fluocinolone acetonide intraocular implant for intermediate uveitis, posterior uveitis, and panuveitis. Ophthalmology 2015;122:1967-1975.
7. The Multicenter Uveitis Steroid Treatment Trial Research Group. Quality of life and risks associated with systemic anti-inflammatory therapy versus fluocinolone acetonide intraocular implant for intermediate uveitis, posterior uveitis, or panuveitis. Ophthalmology 2015;122:1976-1986.
8. pSivida Reports Positive IOP Safety Data in Phase III Trial of Medidu for Posterior Uveitis. [Press Release]. Watertown, MA; pSivida Corp. May 19, 2015.
9. Khurana R. Sustained intravitreal dexamethasone implant for uveitis macular edema: results from the TAHOE Study. Retina Society 2015 Annual Meeting. Paris, France.  October 8 2015.  
10. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. Regulation of immune response by mTOR. Ann Rev Immunol. 2012;30:39-68.
11. Gonzalez J, Harris T, Childs G, Prystowsky MB. Rapamycin blocks IL-2 driven T cell cycle progression while preserving T cell survival. Blood Cells Mol Dis. 2001;27:572-585.